Promoting salt tolerance, growth, and phytochemical responses in coriander (Coriandrum sativum L. cv. Balady) via eco-friendly Bacillus subtilis and cobalt.

In plant production, evaluation of salt stress protectants concerning their potential to improve growth and productivity under saline stress is critical. Bacillus subtilis (Bs) and cobalt (Co) have been proposed to optimize salt stress tolerance in coriander (Coriandrum sativum L. cv. Balady) plants by influencing some physiological activities. The main aim of this work is to investigate the response of (Bs) and (Co) as eco-safe salt stress protectants to resist the effect of salinity, on growth, seed, and essential oil yield, and the most important biochemical constituents of coriander produced under salt stress condition. Therefore, in a split-plot factorial experiment design in the RCBD (randomized complete block design), four levels of salinity of NaCl irrigation water (SA) were assigned to the main plots; (0.5, 1.5, 4, and 6 dS m-1); and six salt stress protectants (SP) were randomly assigned to the subplots: distilled water; 15 ppm (Co1); 30 ppm (Co2); (Bs); (Co1 + Bs); (Co2 + Bs). The study concluded that increasing SA significantly reduced coriander growth and yield by 42.6%, which could be attributed to ion toxicity, oxidative stress, or decreased vital element content. From the results, we recommend that applying Bs with Co (30 ppm) was critical for significantly improving overall growth parameters. This was determined by the significant reduction in the activity of reactive oxygen species scavenging enzymes: superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) and non-enzyme: proline by 5, 11.3, 14.7, and 13.8% respectively, while increasing ascorbic acid by 8% and preserving vital nutrient levels and enhancing plant osmotic potential to buffer salt stress, seed yield per plant, and essential oil yield increased by 12.6 and 18.8% respectively. The quality of essential oil was indicated by highly significant quantities of vital biological phytochemicals such as linalool, camphor, and protein which increased by 10.3, 3.6, and 9.39% respectively. Additional research is suggested to determine the precise mechanism of action of Bs and Co's dual impact on medicinal and aromatic plant salt stress tolerance.

Survival characteristics of Wilms Tumor, a reference developed from a longitudinal cohort study.

BACKGROUND: Wilms tumor (WT) survival has been affected by the evolution in clinical and biological prognostic factors. Significant differences in survival rates indicate the need for further efforts to reduce these disparities. This study aims to evaluate the clinicopathological data impact on survival among patients after Wilm's diagnosis. METHODS: The study utilized the SEERStat Database to identify Wilms tumor patients, applying SEERStat software version 8.3.9.2 for data extraction. Selection criteria involved specific codes based on the International Classification of Diseases for Oncology (ICDO-3), excluding cases with unknown SEER stage, incomplete survival data, unknown size, or lymph node status. Statistical analyses, including Kaplan-Meier estimates and Cox regression models, were conducted using R software version 3.5. Standardized mortality ratios (SMR) were computed with SEER*Stat software, and relative and conditional survival analyses were performed to evaluate long-term survival outcomes. RESULTS: Of 2273 patients diagnosed with Wilms tumor, (1219 patients, 53.6% were females with an average age group of 3-8 years (50.2%). The overall mean survival after five years of diagnosis was 93.6% (2.6-94.7), and the overall mean survival rate was 92.5% (91.3-93.8) after ten years of diagnosis. Renal cancers were identified as the leading cause of death (77.3%), followed by nonrenal cancers (11%) and noncancer causes (11%). Additionally, robust relative survival rates of 98.10%, 92.80%, and 91.3% at one, five, and ten years, respectively, were observed, with corresponding five-year conditional survival rates indicating an increasing likelihood of survival with each additional year post-diagnosis. Univariate Cox regression identified significant prognostic factors: superior CSS for patients below 3 years (cHR 0.48) and poorer CSS for those older than 15 years (cHR 2.72), distant spread (cHR 10.24), regional spread (cHR 3.09), and unknown stage (cHR 4.97). In the multivariate model, age was not a significant predictor, but distant spread (aHR 9.22), regional spread (aHR 2.84), and unknown stage (aHR 4.98) were associated with worse CSS compared to localized tumors. CONCLUSION: This study delving into WT survival dynamics reveals a multifaceted landscape influenced by clinicopathological variables. This comprehensive understanding emphasizes the imperative for ongoing research and personalized interventions to refine survival rates and address nuanced challenges across age, stage, and tumor spread in WT patients.

Cognitive performance and brain volume among survivors of pediatric hematological malignancies: a case-control study.

BACKGROUND: Cognitive dysfunction may be one of the hazardous late effects among survivors of pediatric hematological malignancies. Our study aimed to explore cognitive performance and assess the global and regional brain volume changes in survivors of hematological malignancies. METHODS: This case-control study was conducted on 68 survivors of hematological malignancies, with a median follow-up period of 2 years (ranging from 1 to 6.2 years). Stanford-Binet Test was used for cognitive assessment. A quantitative volumetric assessment of the brain was done using the NeuroQuant Brain Magnetic Resonance. Age and sex-matched 68 children were selected as a comparison group. RESULTS: Cancer survivors showed significantly lower levels of IQ and their subtests than the control group. Global brain atrophy was observed in the majority of the survivors. Many risk factors significantly affected different IQ subtests, such as radiotherapy (RTH), high cumulative doses of methotrexate (MTX), and prednisone. At the same time, low white matter volume (WMV) was observed with higher cumulative doses of MTX and anthracyclines. CONCLUSIONS: Hematological malignancies have a negative impact on cognition. Neurocognitive impairment and related brain changes were evident in those who received RTH, HDMTX, or high cumulative doses of steroids.

Enhancing growth and bioactive metabolites characteristics in Mentha pulegium L. via silicon nanoparticles during in vitro drought stress.

The development and production of secondary metabolites from priceless medicinal plants are restricted by drought stress. Mentha pulegium L. belongs to the Lamiaceae family and is a significant plant grown in the Mediterranean region for its medicinal and aesthetic properties. This study investigated the effects of three polyethylene glycol (PEG) (0, 5, and 10%) as a drought stress inducer and four silicon nanoparticle (SiNP) (0, 25, 50, and 100 ppm) concentrations as an elicitor to overcome the adverse effect of drought stress, on the growth parameters and bioactive chemical composition of M. pulegium L. plants grown in vitro. The experiment was performed as a factorial experiment using a completely randomized design (CRD) consisting of 12 treatments with two factors (3 PEG × 4 SiNPs concentrations), 6 replicates were used for each treatment for a total of 72 experimental units.The percentage of shoot formation was inversely proportional to the PEG concentration; for the highest PEG concentration, the lowest percentage of shoot formation (70.26%) was achieved at 10% PEG. SiNPs at 50 ppm enhanced shoot formation, the number of shoots, shoot height, fresh and dry weight, rosmarinic acid, total phenols, and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity. The methanol extract from M. pulegium revealed the presence of significant secondary metabolites using gas chromatography‒mass spectrometry (GC-MS). The principal constituents of the extract were limonene (2.51, 2.99%), linalool (3.84, 4.64%), geraniol (6.49, 8.77%), menthol (59.73, 65.43%), pulegone (3.76, 2.76%) and hexadecanoic acid methyl ester or methyl palmitate (3.2, 4.71%) for the 0 ppm SiNPs, PEG 0% and 50 ppm SiNPs, and PEG 10%, respectively. Most of the chemical components identified by GC‒MS in the methanol extract were greater in the 50 ppm SiNP and 10% PEG treatment groups than in the control group. SiNP improves drought tolerance by regulating biosynthesis and accumulating some osmolytes and lessens the negative effects of polyethylene glycol-induced drought stress.Based on the results, the best treatment for most of the parameters was 50 ppm SiNPs combined with 10% PEG, the morphological and chemical characteristics were inversely proportional to the PEG concentration, as the highest PEG concentration (10%) had the lowest results. Most parameters decreased at the highest SiNP concentration (100 ppm), except for the DPPH scavenging percentage, as there was no significant difference between the 50 and 100 ppm SiNPs.

Mapping the Grounds for Mortalities in Acute Myeloid Leukemia Through Registry Analyses: A Retrospective Cohort Study of Children, Adolescents, and Young Adults Patients.

Background: Our objective was to identify non-malignant factors that contribute to mortality in children, adolescents and young adults, aiming to improve patient follow-up and reduce mortality rates to achieve better survival outcomes. Methods: We analyzed 8,239 acute myeloid leukemia (AML) cases diagnosed between 2000 and 2019 in the USA. Using version 8.4.0.1 of the Surveillance, Epidemiology, and End Results (SEER)*Stat software, we calculated the standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) for each cause of death. Results: Out of the 3,165 deaths observed in the study population, the majority (2,245;70.9%) were attributed to AML itself, followed by non-AML cancers (573; 18.1%) and non-cancerous causes (347; 10.9%). Conclusions: Patients with AML are at a higher risk of developing other types of cancer and granulocyte deficiencies, which increases the risk of death from non-cancerous causes such as infections. Moreover, treatment for AML carries the risk of cardiac problems. AML is commoner in males than females.

A novel efficient multi-walled carbon nanotubes/gibberellic acid composite for enhancement vase life and quality of Rosa hybrida cv. 'Moonstone'.

The postharvest life of cut flowers is limited, which is a major challenge and varies greatly depending on plant varieties, cut flower stage, flower length of the harvested shoots, and storage conditions including postharvest treatments. As a result, improving the vase life and quality of cut flowers in regulating postharvest characteristics and overcoming these challenges is critical to the horticulture business. Novel engineered nanocomposites were created and tested for possible impacts on flower bud opening, postharvest life extension, longevity regulation, and preservation and enhancement of the strength and appearance of cut flowers. The experiment was conducted as a factorial experiment using a completely randomized design (CRD) with two factors. The first factor was two holding solutions (without or with sucrose at 20 gL-1). The second factor was 12 pulsing treatments for 24 h; distilled water as a control, 75 ppm GA3, multi-walled carbon nanotubes MWCNTs at 10, 20, 30, 40, and 50 ppm, and MWCNTs (10, 20, 30, 40, and 50 ppm)/GA3 (75 ppm) composites; each treatment had 3 replicates, for a total of 72 experimental units. In the present study, gibberellic acid (GA3) was synthesized in functionalized (MWCNT/GA3 composites) as a novel antisenescence agent, and their effect on the vase life quality of cut rose flowers Rosa hybrida cv. 'Moonstone' was compared by assaying several parameters critical for vase life. The adsorption of GA3 on MWCNTs was proven by performing FTIR spectroscopy which ensures that the formation of the MWCNTs/GA3 composite preserves the nanostructure and was examined by high-resolution transmission electron microscopy (HR-TEM). The results revealed that sucrose in the holding solution showed a significant increase in fresh weight, flower diameter, and vase life by 10.5, 10.6, and 3.3% respectively. Applying sucrose with MWCNTs 20 ppm/GA3 75 ppm composites or MWCNTs 20 ppm alone, was critical for the significant increase in flower opening by 39.7 and 28.7%, and longevity by 34.4 and 23.2%, respectively, and significantly increased chlorophyll a, b, total chlorophyll, anthocyanin, total phenolic content, and 2,2-Diphenyl-1-picrylhydrazyl scavenging activity as compared to the control.

Exploration of Tilmicosin Cardiotoxicity in Rats and the Protecting Role of the Rhodiola rosea Extract: Potential Roles of Cytokines, Antioxidant, Apoptotic, and Anti-Fibrotic Pathways.

Tilmicosin (TIL) is a common macrolide antibiotic in veterinary medicine. High doses of TIL can have adverse cardiovascular effects. This study examined the effects of Rhodiola rosea (RHO) that have anti-inflammatory, antioxidant, and anti-fibrotic effects on tilmicosin (TIL)-induced cardiac injury targeting anti-inflammatory, antioxidant, apoptotic, and anti-apoptotic signaling pathways with anti-fibrotic outcomes. Thirty-six male Wistar albino rats were randomly divided into groups of six rats each. Rats received saline as a negative control, CARV 1 mL orally (10 mg/kg BW), and RHO 1 mL orally at 400 mg/kg BW daily for 12 consecutive days. The TIL group once received a single subcutaneous injection (SC) dose of TIL (75 mg/kg BW) on the sixth day of the experiment to induce cardiac damage. The standard group (CARV + TIL) received CARV daily for 12 consecutive days with a single TIL SC injection 1 h after CARV administration only on the sixth day of study and continued for another six successive days on CARV. The protective group (RHO + TIL) received RHO daily for the same period as in CARV + TIL-treated rats and with the dosage mentioned before. Serum was extracted at the time of the rat's scarification at 13 days of study and examined for biochemical assessments in serum lactate dehydrogenase (LDH), cardiac troponin I (cTI), and creatine phosphokinase (CK-MB). Protein carbonyl (PC) contents, malondialdehyde (MDA), and total antioxidant capacity (TAC) in cardiac homogenate were used to measure these oxidative stress markers. Quantitative RT-PCR was used to express interferon-gamma (INF-γ), cyclooxygenase-2 (COX-2), OGG1, BAX, caspase-3, B-cell lymphoma-2 (Bcl-2), and superoxide dismutase (SOD) genes in cardiac tissues, which are correlated with inflammation, antioxidants, and apoptosis. Alpha-smooth muscle actin (α-SMA), calmodulin (CaMKII), and other genes associated with Ca2+ hemostasis and fibrosis were examined using IHC analysis in cardiac cells (myocardium). TIL administration significantly increased the examined cardiac markers, LDH, cTI, and CK-MB. TIL administration also increased ROS, PC, and MDA while decreasing antioxidant activities (TAC and SOD mRNA) in cardiac tissues. Serum inflammatory cytokines and genes of inflammatory markers, DNA damage (INF-γ, COX-2), and apoptotic genes (caspase-3 and BAX) were upregulated with downregulation of the anti-apoptotic gene Bcl-2 as well as the DNA repair OGG1 in cardiac tissues. Furthermore, CaMKII and α-SMA genes were upregulated at cellular levels using cardiac tissue IHC analysis. On the contrary, pretreatment with RHO and CARV alone significantly decreased the cardiac injury markers induced by TIL, inflammatory and anti-inflammatory cytokines, and tissue oxidative-antioxidant parameters. INF-γ, COX-2, OGG1, BAX, and caspase-3 mRNA were downregulated, as observed by real-time PCR, while SOD and Bcl-2 mRNA were upregulated. Furthermore, the CaMKII and α-SMA genes' immune reactivities were significantly decreased in the RHO-pretreated rats.

Magnesium Sulfate in Pediatric Abdominal Cancer Surgery: Safety and Efficacy in Ultrasound-Guided Transversus Abdominis Plane (US-TAP) Block in Conjugation with Levobupivacaine.

Purpose: Magnesium sulfate (MgSO4) may enhance the effects of local anesthetics when used as an adjuvant in peripheral nerve blocks. Our objective was to evaluate efficiency and safety of utilizing MgSO4 alongside levobupivacaine in bilateral ultrasound-guided transversus abdominis plane (US-TAP) block for postoperative pain in pediatric cancer patients who underwent abdominal surgery. Methodology: A randomized double-blinded controlled trial at South Egypt Cancer Institute, Assiut University, Assiut, Egypt, included that 40 pediatric patients with Wilms' tumor or neuroblastoma were randomly allocated to get bilateral (US-TAP) block and divided into two groups; M group: received US-TAP with 0.6 mL/kg levobupivacaine 0.25% + 2 mg/kg MgSO4 and C group: received with 0.6 mL/kg levobupivacaine 0.25% only. FLACC scores (Face, Leg, Activity, Cry, Consolability) were used to evaluate post-operative pain, first analgesic request, total analgesic consumption, adverse effects, as well as hemodynamics were monitored for 24 h and recorded at time points (2, 4, 6, 8, 12, 18, and 24h). Parent's satisfaction at discharge, also, was evaluated. Results: FLACC score in M group was significantly lower than in C group from 4 h to 24 h with the first analgesic request being longer (15.95 ± 1.99 vs 7.70 ± 0.80 (h); p < 0.001) and lower total analgesic consumption (231.75 ± 36.57 vs 576.00 ± 170.71 (mg); p < 0.001) when comparing M group to C group, respectively. Both groups had insignificant differences regarding hemodynamics, parent satisfaction, postoperative agitation, and side effects except vomiting occurred in two patients in the C group and one patient in the M group. Conclusion: We conclude that adding magnesium sulphate as an adjuvant to local anaesthetic in US-TAP block for pain management in pediatric abdominal cancer surgeries resulted in better and longer analgesia, with less consumption of rescue analgesics with no serious side effects.

Evaluating steroid hormone receptor interactions using the live-cell NanoBRET proximity assay.

Steroid hormone receptors play a crucial role in the development and characterization of the majority of breast cancers. These receptors canonically function through homodimerization, but physical interactions between different hormone receptors play a key role in cell functions as well. The estrogen receptor (ERα) and progesterone receptor (PR), for example, are involved in a complex set of interactions known as ERα/PR crosstalk. Here, we developed a valuable panel of nuclear receptor expression plasmids specifically for use in NanoBRET assays to assess nuclear receptor homo- and heterodimerization. We demonstrate the utility of this assay system by assessing ERα/PR physical interaction in the context of the endocrine therapy resistance-associated ERα Y537S mutation. We identify a role of the ERα Y537S mutation beyond that of constitutive activity of the receptor; it also increases ERα/PR crosstalk. In total, the NanoBRET assay provides a novel avenue for investigating hormone receptor crosstalk. Future research may use this system to assess the effects of other clinically significant hormone receptor mutations on hormone receptor crosstalk.

Cancer stem cells as the source of tumor associated myoepithelial cells in the tumor microenvironment developing ductal carcinoma in situ.

The heterogeneous cell population in the stromal microenvironment is considered to be attributed to the multiple sources from which the cells originate. Tumor associated myoepithelial cells (TAMEs) are one of the most important populations in the tumor microenvironment (TME) especially in breast cancer. On the other hand, cancer stem cells (CSCs) have previously been described to be the origin of tumor-associated cellular components in the TME. We prepared a cancer stem cell model converting mouse-induced pluripotent stem cells (miPSCs) in the presence of conditioned medium of breast cancer cell line MDA-MB-231 cells. The converted cells developed tumors progressing into invasive carcinoma with ductal carcinoma in situ (DCIS) like structure when transplanted into mouse mammary fat pads. The primary cultured cells from the tumor further exhibited markers of CSC such as Sox2, Oct3/4, - CD133 and EpCAM, and mammary gland-related TAME markers such as α-smooth muscle actin, cytokeratin 8, whey acidic protein, prolactin receptor and progesterone receptor as well. These results indicated that the CSCs could be an origin of TAMEs contributing to mammary gland epithelial cell differentiation and the progression to invasive carcinoma during tumor development. The gene expression profiles confirmed the enhanced signaling pathways of PI3K/AKT and MAPK, which have been demonstrated to be enriched in the CSC models, together with the estrogen receptor signaling which was peculiar to mammary gland-derived character.

Betulin prevents high fat diet-induced non-alcoholic fatty liver disease by mitigating oxidative stress and upregulating Nrf2 and SIRT1 in rats.

Non-alcoholic fatty liver disease (NAFLD) is a common chronic hepatic disorder characterized by hepatic lipid accumulation. This study explored the effect of betulin (BE), a terpenoid with promising antioxidant, anti-inflammatory and insulin sensitizing effects, on NAFLD induced by high fat diet (HFD). Rats received HFD and BE (15 and 30 mg/kg) for 12 weeks and blood and liver samples were collected for analyses. HFD caused hyperlipidemia, cholesterol and triglycerides accumulation in the liver, hepatocellular ballooning, fibrosis, insulin resistance (IR), lipid peroxidation (LPO), and NF-kB p65 upregulation. BE ameliorated serum and liver lipids, blood glucose and insulin, liver LPO, prevented steatosis and fibrosis, suppressed NF-kB p65 and enhanced antioxidants in HFD-fed rats. BE downregulated acetyl-CoA carboxylase (ACC1) and fatty acid synthase (FAS), and upregulated Nrf2, HO-1 and SIRT1 in the liver of HFD-fed rats. In silico investigations revealed the binding affinity of BE towards FAS, NF-kB, Keap1, HO-1 and SIRT1. In conclusion, BE attenuated HFD-induced NAFLD by ameliorating hyperlipidemia, IR, lipogenesis, liver lipid accumulation, and oxidative stress. The protective effect of BE was associated with enhanced Nrf2/HO-1 signaling and SIRT1.

Activation of SIRT-1 Pathway by Nanoceria Sheds Light on Its Ameliorative Effect on Doxorubicin-Induced Cognitive Impairment (Chemobrain): Restraining Its Neuroinflammation, Synaptic Dysplasticity and Apoptosis.

Chemo fog is one of the most serious health concerns encountered by cancer survivors receiving doxorubicin (DOX)-based chemotherapy. Oxidative stress, neuroinflammation, apoptosis and impairment of synaptic plasticity are regarded as the key factors implicated in DOX-induced cognitive impairment. This research aimed to assess the possible neuroprotective effect of cerium oxide nanoparticles (CeNPs) against DOX-induced neurotoxicity. Forty-eight rats were divided into four groups (12 rats/group): control group, CeNPs group (received oral CeNPs solution (35 mg/kg) daily for 4 weeks), and DOX group (were administered DOX intraperitoneally (2 mg/kg, once/week for 4 weeks)) and DOX+ CeNPs group. The findings revealed that CeNPs mitigated behavioral alterations in DOX-induced cognitive deficit. Additionally, CeNPs alleviated the histopathological abnormalities in hippocampus and ameliorated DOX-induced neuroinflammation by downregulating the expression of NF-κB, TNF-α, IL-1ß and IL6. In addition, CeNPs antagonized the apoptosis through reducing the protein expression of cytochrome c and caspase 3. In addition, it stimulated the antioxidant defense, as indicated by upregulating the expression of the Nrf2, HO-1 and PGC-1α genes. CeNPs improved synaptic plasticity via acting on the BDNF. These actions were related through the modification of SIRT-1 expression. Based on the aforementioned results, CeNPs antagonized the doxorubicin-induced neurodegeneration by its antioxidant, anti-inflammatory and antiapoptotic effects, alongside its SIRT-1 mediated mechanisms.

Functional and Molecular Characters of Cancer Stem Cells Through Development to Establishment.

Cancer stem cells (CSCs) are small subpopulation sharing similar properties like normal stem such as self-renewal and differentiation potential to direct tumor growth. Last few years, scientists considered CSCs as the cause of phenotypic heterogeneity in diverse cancer types. Also, CSCs contribute to cancer metastasis and recurrence. The cellular and molecular regulators influence on the CSCs' phenotype changing their behaviors in different stages of cancer progression. CSC markers play significance roles in cancer diagnosis and characterization. We delineate the cross-talks between CSCs and the tumor microenvironment that supports their intrinsic properties including survival, stemness, quiescence and their cellular and molecular adaptation. An insight into the markers of CSCs specific to organs is described.

Microenvironment of mammary fat pads affected the characteristics of the tumors derived from the induced cancer stem cells.

Breast cancer is the first common cause of cancer-related death in women worldwide. Since the malignancy and aggressiveness of breast cancer have been correlated with the presence of breast cancer stem cells, the establishment of a disease model with cancer stem cells is required for the development of a novel therapeutic strategy. Here, we aimed to evaluate the availability of cancer stem cell models developed from mouse induced pluripotent stem cells with the conditioned medium of different subtypes of breast cancer cell lines, the hormonal-responsive T47D cell line and the triple-negative breast cancer BT549 cell line, to generate in vivo tumor models. When transplanted into the mammary fat pads of BALB/c nude mice, these two model cells formed malignant tumors exhibiting pronounced histopathological characteristics similar to breast cancers. Serial transplantation of the primary cultured cells into mammary fat pads evoked the same features of breast cancer, while this result was perturbed following subcutaneous transplantation. The tumors formed in the mammary fat pads exhibited immune reactivities to prolactin receptor, progesterone receptor, green florescent protein, Ki67, CD44, estrogen receptor α/ß and cytokeratin 8, while all of the tumors and their derived primary cells exhibited immunoreactivity to estrogen receptor α/ß and cytokeratin 8. Cancer stem cells can be developed from pluripotent stem cells via the secretory factors of cancer-derived cells with the capacity to inherit tissue specificity. However, cancer stem cells should be plastic enough to be affected by the microenvironment of specific tissues. In summary, we successfully established a breast cancer tumor model using mouse induced pluripotent stem cells developed from normal fibroblasts without genetic manipulation.

Increase in polymorphonuclear myeloid-derived suppressor cells and regulatory T-cells in children with B-cell acute lymphoblastic leukemia.

Our study aimed to evaluate the levels of MDSCs and Tregs in pediatric B-cell acute lymphoblastic leukemia (B-ALL), their relation to patients' clinical and laboratory features, and the impact of these cells on the induction response. This study included 31 pediatric B-ALL patients and 27 healthy controls. All patients were treated according to the protocols of the modified St. Jude Children's Research Hospital total therapy study XIIIB for ALL. Levels of MDSCs and Tregs were analyzed using flow cytometry. We observed a reduction in the levels of CD4 + T-cells and an increase in both the polymorphonuclear MDSCs (PMN-MDSCs) and Tregs. The frequencies of PMN-MDSCs and Tregs were directly related to the levels of peripheral and bone marrow blast cells and CD34 + cells. Complete postinduction remission was associated with reduced percentages of PMN-MDSCs and Tregs, with the level of PMN-MDCs in this subpopulation approaching that of healthy controls. PMN-MDSCs and Tregs jointly play a critical role in maintaining an immune-suppressive state suitable for B-ALL tumor progression. Thereby, they could be independent predictors of B-ALL progress, and finely targeting both PMN-MDSCs and Tregs may be a promising approach for the treatment of B-ALL.

Tumor-associated macrophages derived from cancer stem cells.

Macrophages are the most abundant immune cells in the microenvironment of solid tumors. The present study displayed histological and immunohistochemical analyses of a malignant tumor model developed from cancer stem cells (CSCs) converted from human induced pluripotent stem cells (hiPSCs) in a cancer microenvironment prepared from the conditioned medium (CM) of a pancreatic cancer cell line. We focused on the localization and the origin of tumor-associated macrophages (TAMs), To the best of our knowledge this may be the first study to suggest the potential differentiation of CSCs to TAMs. hiPSCs were converted into CSCs in the presence of CM from PK8 cells. CSCs were then transplanted in vivo and formed primary tumors. Primary cultures for these tumors were serially transplanted again to obtain secondary tumors. Secondary tumors exhibited histopathological features of malignancy. Cells derived from tumors maintained the expression of endogenous stemness markers and pancreatic CSCs markers. Simultaneously, high immunoreactivity to anti-mouse CD68, anti-human CD68, CD206 and CD11b antibodies were detected revealing that the tumor tissue derived from CSCs was enriched for macrophages which can originate from both human and mouse cells. The model of CSCs highlighted the possibility of CSCs to differentiate into TAMs.

Analgesic Effect of Intrathecal Fentanyl vs Dexmedetomidine as Adjuvants to Bupivacaine Following Abdominal Surgery for Cancer in Children, a Randomized Trial.

BACKGROUND: Intrathecal fentanyl in spinal anesthesia improves intra- and postoperative analgesia. Dexmedetomidine is a fascinating adjuvant with regards to neuraxial anesthesia in children experiencing surgery for abdominal malignancy. PATIENTS AND METHODS: After endorsement by the institutional reviewing board (IRB) and guardians' written informed consent, this research was carried out on 60 pediatric malignancy patients scheduled for major abdominal surgery. Children were randomly distributed into three groups (20 patients each): Group C: given 2 mL of bupivacaine 0.5% (0.4 mg/kg) intrathecally, injected gradually over 20 seconds. Group F: the same as group C, plus fentanyl 0.2 µg/kg. Group D: the same as group C, plus dexmedetomidine 0.2 µg/kg. Pain at zero, two, four, six, 12, 18, and 24 hours postoperatively was evaluated by Face, Legs, Activity, Crying, and Consolability (FLACC) score. First analgesic request and postoperative unfavorable effects were recorded for 24 hours postoperatively. RESULTS: A significant decrease was recognized in the mean FLACC score in groups D and F at six, eight, and 12 hours postoperatively, in contrast to group C (P ≤ 0.05). First analgesic request was significantly prolonged in group D (7.67 ± 0.57 hours), in contrast to groups F and C (5.40 ± 1.09 hours and 4.23 ± 3.27 hours, respectively, P < 0.04). Paracetamol utilization was significantly decreased in group D (316.67 ± 28.86 mg), in contrast to group C (391.00 ± 52.00 mg, P < 0.03), without a significant difference between group F (354.44 ± 46.67 mg) and groups D and C (P > 0.05). CONCLUSIONS: Adding dexmedetomidine and fentanyl to intrathecal bupivacaine improved postoperative analgesia following abdominal surgery for cancer in children, with better overall analgesia of dexmedetomidine compared with fentanyl.

Paclitaxel and Sorafenib: The Effective Combination of Suppressing the Self-Renewal of Cancer Stem Cells.

"Combination therapy", which is a treatment modality combining two or more therapeutic agents, is considered a cornerstone of cancer therapy. The combination of anticancer drugs, of which functions are different from the other, enhances the efficiency compared to the monotherapy because it targets cancer cells in a synergistic or an additive manner. In this study, the combination of paclitaxel and sorafenib in low concentration was evaluated to target cancer stem cells, miPS-BT549cmP and miPS-Huh7cmP cells, developed from mouse induced pluripotent stem cells. The synergistic effect of paclitaxel and sorafenib on cancer stem cells was assessed by the inhibition of proliferation, self-renewal, colony formation, and differentiation. While the IC50 values of paclitaxel and sorafenib were approximately ranging between 250 and 300 nM and between 6.5 and 8 µM, respectively, IC50 of paclitaxel reduced to 20 and 25 nM, which was not toxic in a single dose, in the presence of 1 µM sorafenib, which was not toxic to the cells. Then, the synergistic effect was further assessed for the potential of self-renewal of cancer stem cells by sphere formation ability. As a result, 1 µM of sorafenib significantly enhanced the effect of paclitaxel to suppress the number of spheres. Simultaneously, paclitaxel ranging in 1 to 4 nM significantly suppressed not only the colony formation but also the tube formation of the cancer stem cells in the presence of 1 µM sorafenib. These results suggest the combination therapy of paclitaxel and sorafenib in low doses should be an attractive approach to target cancer stem cells with fewer side effects.

Revisiting Cancer Stem Cells as the Origin of Cancer-Associated Cells in the Tumor Microenvironment: A Hypothetical View from the Potential of iPSCs.

The tumor microenvironment (TME) has an essential role in tumor initiation and development. Tumor cells are considered to actively create their microenvironment during tumorigenesis and tumor development. The TME contains multiple types of stromal cells, cancer-associated fibroblasts (CAFs), Tumor endothelial cells (TECs), tumor-associated adipocytes (TAAs), tumor-associated macrophages (TAMs) and others. These cells work together and with the extracellular matrix (ECM) and many other factors to coordinately contribute to tumor growth and maintenance. Although the types and functions of TME cells are well understood, the origin of these cells is still obscure. Many scientists have tried to demonstrate the origin of these cells. Some researchers postulated that TME cells originated from surrounding normal tissues, and others demonstrated that the origin is cancer cells. Recent evidence demonstrates that cancer stem cells (CSCs) have differentiation abilities to generate the original lineage cells for promoting tumor growth and metastasis. The differentiation of CSCs into tumor stromal cells provides a new dimension that explains tumor heterogeneity. Using induced pluripotent stem cells (iPSCs), our group postulates that CSCs could be one of the key sources of CAFs, TECs, TAAs, and TAMs as well as the descendants, which support the self-renewal potential of the cells and exhibit heterogeneity. In this review, we summarize TME components, their interactions within the TME and their insight into cancer therapy. Especially, we focus on the TME cells and their possible origin and also discuss the multi-lineage differentiation potentials of CSCs exploiting iPSCs to create a society of cells in cancer tissues including TME.

[Preemptive nebulized ketamine for pain control after tonsillectomy in children: randomized controlled trial]. / Uso preventivo de cetamina nebulizada para controle da dor após amigdalectomia em crianças: estudo randômico e controlado.

OBJECTIVES: The administration of ketamine as nebulized inhalation is relatively new and studies on nebulized ketamine are scarce. We aimed to investigate the analgesic efficacy of nebulized ketamine (1 and 2mg.kg-1) administered 30min before general anesthesia in children undergoing elective tonsillectomy in comparison with intravenous ketamine (0.5mg.kg-1) and saline placebo. METHODS: One hundred children aged (7-12) years were randomly allocated in four groups (n=25) receive; Saline Placebo (Group C), Intravenous Ketamine 0.5mg.kg-1 (Group K-IV), Nebulized Ketamine 1mg.kg-1 (Group K-N1) or 2mg.kg-1 (Group K-N2). The primary endpoint was the total consumption of rescue analgesics in the first 24h postoperative. RESULTS: The mean time to first request for rescue analgesics was prolonged in K-N1 (400.9±60.5min, 95% CI 375.9-425.87) and K-N2 (455.5±44.6min, 95% CI 437.1-473.9) groups compared with Group K-IV (318.5±86.1min, 95% CI 282.9-354.1) and Group C (68.3±21.9min, 95% CI 59.5-77.1; p<0.001), with a significant difference between K-N1 and K-N2 Groups (p<0.001). The total consumption of IV paracetamol in the first 24h postoperative was reduced in Group K-IV (672.6±272.8mg, 95% CI 559.9-785.2), Group K-N1 (715.6±103.2mg, 95% CI 590.4-840.8) and Group K-N2 (696.6±133.3mg, 95% CI 558.8-834.4) compared with Control Group (1153.8±312.4mg, 95% CI 1024.8-1282.8; p<0.001). With no difference between intravenous and Nebulized Ketamine Groups (p=0.312). Patients in intravenous and Nebulized Ketamine Groups showed lower postoperative VRS scores compared with Group C (p<0.001), no differences between K-IV, K-N1 or K-N2 group and without significant adverse effects. CONCLUSION: Preemptive nebulized ketamine was effective for post-tonsillectomy pain relief. It can be considered as an effective alternative route to IV ketamine.